Urinary incontinence is the involuntary discharge of urine. This occurs in an uncontrolled manner when the pressure within the urinary bladder exceeds the pressure needed to close the ureter. Causes can be on the one hand an increased internal pressure in the bladder (e.g. due to detrusor instability) with the consequence of urgency incontinence and on the other hand a reduced sphincter pressure (e.g. following giving birth or surgical interventions) with the consequence of stress incontinence. The detrusor is the coarsely bundled multilayered bladder wall musculature, contraction of which leads to the discharge of urine. The sphincter is the closing muscle of the urethra. Mixed forms of these types of incontinence and so-called overflow incontinence (e.g. in cases of benign prostate hyperplasia) or reflex incontinence (e.g. following damage to the spinal cord) also occur. Further details in this respect are found in Chutka, D. S. and Takahashi, PY., 1998, drugs 560: 587-595.
The urge to urinate is caused by increased bladder muscle tension as the bladder capacity is approached (or exceeded), prompting the discharge of urine (miction). The increased tension acts as a stimulus to miction. An increased urge to urinate is understood in the context of the present invention as meaning the occurrence of a premature or increased and sometimes even painful urge to urinate up to the so-called strangury. This consequently leads to significantly more frequent miction. Causes can be, inter alia, inflammations of the urinary bladder and neurogenic bladder disorders, and also bladder tuberculosis. However, all causes have not yet been clarified.
An increased urge to urinate and urinary incontinence are perceived as extremely unpleasant and there is a clear need among persons afflicted by these conditions to achieve an improvement which is as long-term as possible.
An increased urge to urinate and in particular urinary incontinence are conventionally treated with substances involved in the reflexes of the lower urinary tract (Wein, A. J., 1998, Urology 51 (suppl. 21): 43-47). These are usually medicaments which have an inhibiting action on the detrusor muscle, which is responsible for the internal pressure in the bladder. These medicaments are e.g. parasympatholytics, such as oxybutynin, propiverine or tolterodine, tricyclic antidepressants, such as imipramine, or muscle relaxants, such as flavoxate. Other medicaments, which in particular increase the resistance of the urethra or of the neck of the bladder, show affinities for α-adrenoreceptors, such as ephedrine, for β-adrenoreceptors, such clenbutarol, or are hormones, such as estradiol. Certain opioids, e.g., diarylmethylpiperazines and piperidines, are also described for this indication in WO 93/15062. For tramadol, a positive effect on bladder function has been demonstrated in a rat model of rhythmic bladder contractions (Nippon-Shinyaku, WO 98/46216).
Generally, treatment of increased urge to urinate or urinary incontinence requires very long-term uses of medicaments. This is in contrast to many other situations where analgesics are employed. Urinary incontinence patients are faced with a condition which is very unpleasant but not intolerable. Therefore treatment of this condition must ensure—even more so than with other use of analgesics—that side effects of the analgesics are avoided, if the patient is not to be forced to exchange one evil for another. In addition, analgesic actions of the pharmaceutical compositions are largely undesirable and should be avoided during long-term treatment of urinary incontinence.